Processes for preparing intermediates of inhibitors of enkephalinase and angiotensin converting enzyme and intermediates thereof

ABSTRACT

The present invention relates to novel processes for preparing intermediates of the formula I ##STR1## and to novel intermediates thereof which are useful in the preparation of inhibitors of enkephalinase and angiotensin converting enzyme.

This is a division, of application Ser. No. 08/535,403, filed Oct. 24,1995, now U.S. Pat. No. 5,641,880, which is a continuation-in-part ofapplication Ser. No. 08/360,915, filed Dec. 21, 1994, now abandoned,which is herein incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to novel processes for preparing compoundsof the formula I, ##STR2## which are useful intermediates for preparinginhibitors of enkephalinase and angiotensin converting enzyme, including4S- 4α, 7α(R*), 12bβ!!-7-(1-oxo-2(S)-thio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine-4-carboxylic acid and 4S- 4α, 7α(R*), 12bβ!!-7-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine-4-carboxylic acid and pharmaceutically acceptablesalts thereof (European Patent Application No. 0 481 522 A1, published22 Apr. 1992, 209th ACS National Meeting, Division of MedicinalChemistry, Abst. No. 161 (1995), and European Patent Application No. 657453 A1, published 14 Jun. 1995) and to novel intermediates thereof.

SUMMARY OF THE INVENTION

The present invention provides a novel process for preparing a compoundof formula I ##STR3## wherein G completes an aromatic ring selected fromthe group consisting of ##STR4## wherein X₁ is selected from the groupconsisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy;

comprising:

(a) reacting a phthalimido aryl amino acid amide of the formula ##STR5##wherein Ar is a radical selected from the group consisting of ##STR6##wherein X₁ is selected from the group consisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of phenyl and C₁ -C₄ alkoxy;

with glutaric dialdehyde to give a 1,4-dihydropyridine derivative of theformula ##STR7## wherein Ar is as defined above;

(b) reacting the 1,4-dihydropyridine derivative with an appropriatecyclizing acid to give a 1,2,6,7,8,12b hexahydro-6-oxopyrido 2,1-a!2!azepine of the formula ##STR8## wherein G is as defined above;

(c) reacting the 1,2,6,7,8,12b hexahydro-6-oxopyrido 2,1-a! 2!azepinewith carbon monoxide in the presence of a suitable acid followed byhydration.

In addition, the present invention provides a novel process forpreparing a compound of formula I ##STR9## wherein G completes anaromatic ring selected from the group consisting of ##STR10## wherein X₁is selected from the group consisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy;

comprising:

(a) reacting a phthalimido aryl amino acid derivative of the formula##STR11## wherein A is selected from the group consisting of --OH, --Cl,--Br, anhydride, mixed anhydride, and activated ester;

Ar is a radical selected from the group consisting of ##STR12## whereinX₁ is selected from the group consisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of phenyl and C₁ -C₄ alkoxy;

with 2-cyano-1,2,3,4-tetrahydro-pyridine to give a2-cyano-1,2,3,4-tetrahydro-pyridine derivative of the formula ##STR13##wherein Ar is as defined above; (b) reacting the2-cyano-1,2,3,4-tetrahydro-pyridine derivative with an appropriatecyclizing acid to give a 4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine of the formula ##STR14## wherein G is as definedabove; (c) hydrolyzing the4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido 2,1-a! 2!benzazepine.

The present invention provides a novel compound of the formula:##STR15## wherein Ar is a radical selected from the group consisting of##STR16## wherein X₁ is selected from the group consisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy.

In addition, the present invention provides a novel compound of theformula: ##STR17## wherein G completes an aromatic ring selected fromthe group consisting of ##STR18## wherein X₁ is selected from the groupconsisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy.

In addition, the present invention provides a novel compound of theformula: ##STR19## wherein Ar is a radical selected from the groupconsisting of ##STR20## wherein X₁ is selected from the group consistingof S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy.

In addition, the present invention provides a novel compound of theformula: ##STR21## wherein G completes an aromatic ring selected fromthe group consisting of ##STR22## wherein X₁ is selected from the groupconsisting of S and NH;

X₂ is selected from the group consisting of S, O, and NH; and

R is selected from the group consisting of hydrogen, hydroxy, phenyl,and C₁ -C₄ alkoxy.

DETAILED DESCRIPTION OF THE INVENTION

As used in this application:

a) the designation "" refers to a bond that protrudes forward out of theplane of the page;

b) the designation "" refers to a bond that protrudes backward out ofthe plane of the page;

c) the designation "" refers to a bond for which the stereochemistry isnot designated;

d) the term "C₁ -C₄ alkoxy" refer to a straight or branched alkoxy groupcontaining from 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, t-butoxy, etc;

e) the term "phenyl" refers to a radial of the formula ##STR23## f) thedesignation ##STR24## refers to a thienyl or pyrrolyl and it isunderstood that the radical may be attached at either the 2-position orthe 3-position;

g) the designation ##STR25## refers to an indolyl, benzthienyl, orbenzfuryl and it is understood that the radical may attached at eitherthe 2-position or the 3-position;

h) the designation ##STR26## refers to a naphthyl it is understood thatthe radical can be attached at either the 1-position or the 2-position;

i) it is understood that when G completes an aromatic ring ##STR27##that the compound of formula I is of the formula ##STR28## j) it isunderstood that when G completes an aromatic ring ##STR29## that thecompound of formula I is of the formula ##STR30## k) it is understoodthat when G completes an aromatic ring ##STR31## that the compound offormula I is of the formula ##STR32## l) it is understood that when Gcompletes an aromatic ring ##STR33## that the compound of formula I isof the formula ##STR34## m) it is understood that when G completes anaromatic ring ##STR35## that the compound of formula I is of the formula##STR36## n) it is understood that when G completes an aromatic ring##STR37## that the compound of formula I is of the formula ##STR38## o)it is understood that when G completes an aromatic ring ##STR39## thatthe compound of formula I is of the formula ##STR40## p) the term"pharmaceutically acceptable salts" refers to either acid addition saltsor to base addition salts.

The expression "pharmaceutically acceptable acid addition salts" isintended to apply to any non-toxic organic or inorganic acid additionsalt of inhibitors of enkephalinase and angiotensin converting enzyme,including 4S- 4α, 7α(R*), 12bβ!!-7-(1-oxo-2(S)-thio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid or 4S- 4α, 7α(R*), 12bβ!!-7-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid or any intermediates thereof.Illustrative inorganic acids which form suitable salts includehydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metalsalts such as sodium monohydrogen orthophosphate, and potassium hydrogensulfate. Illustrative organic acids which form suitable salts includethe mono-, di-, and tricarboxylic acids. Illustrative of such acids arefor example, acetic, glycolic, lactic, pyruvic, malonic, succinic,glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic,hydroxymaleic, benzoic, hydroxy-benzoic, phenylacetic, cinnamic,salicyclic, 2-phenoxy-benzoic, and sulfonic acids such asp-toluenesulfonic acid, methane sulfonic acid and 2-hydroxyethanesulfonic acid. Such salts can exist in either a hydrated orsubstantially anhydrous form.

The expression "pharmaceutically acceptable basic addition salts" isintended to apply to any non-toxic organic or inorganic basic additionsalts of inhibitors of enkephalinase and angiotensin converting enzyme,including 4S- 4α, 7α(R*), 12bβ!!-7-(1-oxo-2(S)-thio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid or 4S- 4α, 7α(R*), 12bβ!!-7-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid or any intermediates thereof.Illustrative bases which form suitable salts include alkali metal oralkaline-earth metal hydroxides such as sodium, potassium, calcium,magnesium, or barium hydroxides; ammonia, and aliphatic, cyclic, oraromatic organic amines such as methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, isopropyldiethylamine,pyridine and picoline.

As is appreciated by one of ordinary skill in the art, the methodologydisclosed herein can be used to prepare all isomers at the 4-positionand 7-position of instant intermediates, including 7-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine-4-carboxylic acid and thereby the isomers of theinhibitors of enkephalinase and angiotensin converting enzyme producedtherefrom. The stereochemistry at the 7-position of the intermediates isdetermined by the stereochemistry of the phthalimido aryl amino acidamide or the activated phthalimido aryl amino acid derivative selected.The specific 4-position stereoisomers can be resolved and recovered bytechniques known in the art, such as chromatography on silica gel or ona chiral stationary phase, or fractional recrystallization of the4-position carboxylic acids or derivatives thereof as described herein;in European Patent Application No. 0 481 522 A1, published 22 Apr. 1992;Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Wilen, Wiley(1994); and in Enantiomers, Racemates, and Resolutions, J. Jacques, A.Collet, and S. H. Wilen, Wiley (1981).

A general synthetic procedure is set forth in Scheme A. In Scheme A, allsubstituents unless otherwise indicated, are as previously defined.Starting materials, reagents, techniques and procedures used in Scheme Aare well known and appreciated by one of ordinary skill in the art.##STR41##

In Scheme A, step 1, an appropriate phthalimido aryl amino acidderivative of structure (1) is contacted with ammonia to give aphthalimido aryl amino acid amide of structure (2) as is well known inthe art.

In Scheme A, step a, an appropriate phthalimido aryl amino acid amide ofstructure (2) is contacted with glutaric dialdehyde to give a1,4-dihydro-pyridine derivative of structure (3).

An appropriate phthalimido aryl amino acid amide derivative of structure(2) are readily available or are readily derived from aromatic aminoacids which are well known in the art. Examples of aromatic amino acidswhich are useful in this instant process include: phenylalanine,tryptophan, tyrosine and its ether derivatives, thien-2-ylalanine,3-thienylalanine, fur-2-ylalanine, fur-3-ylalanine,benzthien-2-ylaianine, indol-2-ylalanine, etc. The Peptides, vol. 5, E.Gross and J. Meienhoffer ed. (Academic Press, 1983). In addition,aromatic amino acids can be obtained by methods known in the art oranalogously known in the art, such as D. A. Evans, et al. J. Am. Chem.Soc., 112, 4011-4030 (1990); S. Ikegami et al. Tetrahedron 44, 5333-5342(1988); W. Oppolzer et al. Tet. Lets. 30, 6009-6010 (1989); Synthesis ofOptically Active α-Amino-Acids, R. M. Williams (Pergamon Press, Oxford1989); M. J. O'Donnell ed.: α-Amino-Acid Synthesis, Tetrahedron Symposiain print, No. 33, Tetrahedron 44, No. 17 (1988); U. Schokopf, Pure Appl.Chem. 55, 1799 (1983); U. Hengartner et al. J. Org. Chem., 44, 3748-3752(1979); M. J. O'Donnell et al. Tet. Lets., 2641-2644 (1978); M. J.O'Donnell et al. Tet. Lets. 23, 4255-4258 (1982); M. J. O'Donnell et al.J. Am. Chem. Soc. 110, 8520-8525 (1988).

An appropriate phthalimido aryl amino acid amide of structure (2) is onein which the stereochemistry is as desired in the final product and Aris as required to give G as desired in the final product. It isunderstood that glutaric dialdehyde can be generated in the reactionmixture from a suitable glutaric dialdehyde equivalent. Suitableglutaric dialdehyde equivalents include acetals of glutaric dialdehyde,hydrated forms of glutaric dialdehyde, and the like.

For example, an appropriate phthalimido aryl amino acid amide ofstructure (2) is contacted with from about 0.9 to 1.2 molar equivalentsof glutaric dialdehyde. The reaction is carried out in a suitablesolvent, such as dichloromethane. The reaction is carried out underacidic catalysis. Suitable catalysts are well known in the art andinclude p-toluenesulfonic acid. The reaction is carried out at fromambient temperature to the refluxing temperature of the solvent. Thereaction is carried out with the removal of water by methods well knownin the art, such as by azeotrope, by passing the refluxate over orthrough a drying agent, such as phosphorous pentoxide or by carrying outthe reaction in the presence of a suitable non-reactive drying agent,such as 3 Å molecular sieves, 4 Å molecular sieves, MgSO₄, and the like.Generally, the reaction requires from 2 hours to 4 days. The product canbe isolated and purified by techniques well known in the art, such asextraction, evaporation, chromatography, and recrystallization.

In Scheme A, step b, an appropriate 1,4-dihydropyridine derivative ofstructure (3) is contacted with an appropriate cyclizing acid to give a1,2,6,7,8,12b hexahydro-6-oxopyrido 2,1-a! 2!azepine of structure (4).

For example, an appropriate 1,4-dihydro-pyridine derivative of structure(3) is contacted with an appropriate cyclizing acid. An appropriatecyclizing acid is one which allows for the formation of product withoutleading to significant degradation of either the starting material orthe product. Examples appropriate cyclizing acids include, sulfuricacid, trifluoromethanesulfonic acid, sulfuric acid/trifluoroaceticanhydride mixtures, and trifluoromethanesulfonic acid/trifluoroaceticanhydride mixtures. The reaction is carried out neat in the appropriatecyclizing acid selected or in a suitable aprotic solvent, such asdichloromethane. The reaction is carried out at temperatures of from 10°C.-40° C. Generally the reaction requires from 1 to 8 hours. The productcan be isolated and purified by techniques well known in the art, suchas extraction, evaporation, chromatography, and recrystallization.

In Scheme A, step c, an appropriate 1,2,6,7,8,12b hexahydro-6-oxopyrido2,1-a! 2!azepine of structure (4) is contacted with carbon monoxide inthe presence of a suitable acid followed by hydration to give a compoundof the formula I.

For example, an appropriate 1,2,6,7,8,12b hexahydro-6-oxopyrido 2,1-a!2!azepine of structure (4) is contacted with an excess of carbonmonoxide in the presence of a suitable acid, such as sulfuric acid,followed by hydration. The reaction is carried out using the suitableacid selected as solvent. The reaction may be carried out in a suitablepressure vessel to prevent the escape of carbon monoxide. Carbonmonoxide may be introduced as a gas or may be generated in the reactionvessel by methods well known in the art, such as the decomposition offormic acid. The reaction is carried out at temperatures of from 0° to100° C. The reaction may be carried out at pressures of from atmosphericpressure to 900 psi. When the reaction is carried out at a pressurewhich is greater than atmospheric the use of a suitable pressure vessel,such as sealed or sealable tubes, a pressure reactor or an autoclave, isrequired. Generally the reaction requires from 1 to 48 hours. Theaddition of carbon monoxide is followed by hydration which isaccomplished by the addition of water. The product can be isolated andpurified by techniques well known in the art, such as extraction,evaporation, chromatography, and recrystallization.

A general synthetic procedure is set forth in Scheme B. In Scheme B, allsubstituents unless otherwise indicated, are as previously defined.Starting materials, reagents, techniques, and procedures used in SchemeB are well known and appreciated by one of ordinary skill in the art.##STR42##

In Scheme B, step a, an appropriate phthalimido aryl amino acidderivative of structure (1) is contacted with2-cyano-1,2,3,4-tetrahydro-pyridine to give a2-cyano-1,2,3,4-tetrahydro-pyridine derivative of structure (6).

An appropriate phthalimido aryl amino acid derivative are readilyavailable or are readily derived from aromatic amino acids which arewell known in the art as described in Scheme A, step a.

An appropriate phthalimido aryl amino acid derivative is one in whichthe stereochemistry is as desired in the final product, Ar is asrequired to give G as desired in the final product, and the group A isan activating group which can be displaced by2-cyano-1,2,3,4-tetrahydropyridine in an amidation reaction. Anamidation reaction may proceed through an acid, A is --OH; or an acidhalide, such as an acid chloride, A is --Cl; or acid bromide, A is --Br;or an activated intermediate; such as an anhydride; or a mixed anhydrideof substituted phosphoric acid, such as dialkylphosphoric acid,diphenylphosphoric acid, halophosphoric acid; of aliphatic carboxylicacid, such as formic acid, acetic acid, propionic acid, butyric acid,isobutyric acid, pivalic acid, 2-ethylbutyric acid, trichloroaceticacid, trifluoroacetic acid, and the like; of aromatic carboxylic acids,such as benzoic acid and the like; of an activated ester, such as phenolester, p-nitrophenol ester, 2,4-dinitrophenol ester, pentafluorophenolester, pentachlorophenol ester, N-hydroxysuccinimide ester,N-hydroxyphthalimide ester, 1-hydroxy-1H-benztriazole ester, and thelike; activated amide, such as imidazole, dimethylpyrazole, triazole, ortetrazole; or an intermediate formed in the presence of coupling agents,such as dicyclohexylcarbodiimide or1-(3-dimethyaminopropyl)-3-ethyicarbodiimide. Acid halides and activatedintermediates may be prepared and used without isolation. Alternately,acid halides and activated intermediates may be prepared and isolatedbut not purified before use. The use and formation of acid halides andactivated intermediates is well known and appreciated in the art.

For example, an appropriate phthalimido aryl amino acid derivative ofstructure (1) in which A is --Cl is contacted with a molar excess of2-cyano-1,2,3,4-tetrahydro-pyridine which can be generated in situ byreacting 2,6-dicyanopiperidine with a suitable base such as potassiumt-butoxide. The reaction is carried out in a suitable solvent, such as,tetrahydrofuran. The amide formation reaction is carried out using asuitable base, such as N-methylmorpholine. The reaction is carried outat temperatures of from -50° C. to 40° C. and generally requires from 1hour to 5 hours. The product can be isolated and purified by techniqueswell known in the art, such as filtration, evaporation, extraction,chromatography, and recrystallization.

In Scheme B, step b, an appropriate 2-cyano-1,2,3,4-tetrahydro-pyridinederivative of structure (6) is contacted with an appropriate cyclizingacid to give a 4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido 2,1-a!2!benzazepine of structure (7).

An appropriate cyclizing acid is one which allows for the formation ofproduct without leading to significant degradation of either thestarting material or the product. Examples of appropriate cyclizingacids include, sulfuric acid, trifluoromethanesulfonic acid, sulfuricacid/trifluoroacetic anhydride mixtures, and trifluoromethanesulfonicacid/trifluoroacetic anhydride mixtures.

For example, an appropriate 2-cyano-1,2,3,4-tetrahydropyridinederivative of structure (6) is contacted with an appropriate cyclizingacid. The reaction is carried out neat in the appropriate cyclizing acidselected or in a suitable aprotic solvent, such as dichloromethane. Thereaction is carried out at temperatures of from 10° C.-40° C. andgenerally requires from 1 to 18 hours. It is preferred that the productof this step, obtained in solution, be used without isolation, however,the product can be isolated and purified by techniques well known in theart, such as extraction, evaporation, chromatography, andrecrystallization.

In Scheme B, step c, an appropriate4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido 2,1-a! 2!benzazepine ofstructure (7) is hydrolyzed to give a compound of the formula I.

For example, an appropriate4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido 2,1-a! 2!benzazepine ofstructure (7) is contacted with water. The reaction is carried out inthe presence of a suitable acid catalyst. A suitable acid catalyst isone which allows for the hydrolysis of a cyano group, under the reactionconditions, to a carboxylic acid without removing the phthalimide groupor hydrolyzing the cyclic amide bond. Suitable acid catalysts are wellknown in the art and include, sulfuric acid, trifluoromethanesulfonicacid, trifluoromethanesulfonic acid/trifluoroacetic acid mixtures andsulfuric acid/trifluoroacetic anhydride mixtures. When the product ofthe previous step is used without isolation the appropriate cyclizingacid selected may be used as the suitable acid catalyst for thehydrolysis. The reaction is carried out at temperatures of from about10° C. to about 40° C. Generally the reaction requires from 10 minutesto 2 hours. The product can be isolated and purified by techniques wellknown in the art, such as extraction, evaporation, chromatography, andrecrystallization.

The following examples present typical syntheses as described in SchemesA and B. These examples and preparations are understood to beillustrative only and are not intended to limit the scope of theinvention in any way. As used in the following examples andpreparations, the following terms have the meanings indicated: "mg"refers to milligrams, "g" refers to grams, "kg" refers to kilograms,"mmol" refers to millimoles, "mol" refers to moles, "L" refers tomicroliters, "mL" refers to milliliters, "L" refers to liters, "°C."refers to degrees Celsius, "mp" refers to melting point, "dec" refers todecomposition, " α!² _(D) ⁰ " n refer to specific rotation of the D lineof sodium at 20° C. obtained in a 1 decimeter cell, "c" refers toconcentration in g/100 mL, "M" refers to molar, "L" refers to liter,"2-PrOH" refers to isopropanol, "MeOH" refers to methanol, "R_(f) "refers to retention factor, "TLC" refers to thin layer chromatography,"psi" refers to pounds per square inch.

PREPARATION 1 Synthesis of N-Phthaloyl-(S)-phenylalanine, acid chloride

Combine phthalic anhydride (1.82 kg, 12.3 mole), (S)-phenylalanine (1.84kg, 11.1 moles) and anhydrous dimethylformamide (2.26 L). Stir at115°-120° C. for 2 hours under a nitrogen atmosphere. Pour into rapidlystirred water (32.6 L) and cool overnight at 0° C. Filter, wash withcold water (2×2 L), and air dry. Dissolve in a mixture of 9 A ethanol(8.05 L) and water (8.05 L) and heat at reflux temperature. Gravityfilter, cool to ambient temperature and refrigerate overnight at about0° C. Filter the crystallized product, wash with cold 50:50 9 Aethanol/water (2×2 L) and air dry to yield 2.96 kg (90.3%) ofN-phthaloyl-(S)-phenylalanine; mp 177°-179° C.

Combine N-phthaloyl-(S)-phenylalanine (50.2 g, 0.17 mol), methylenechloride (660 mL) and dimethylformamide (0.5 mL) under a nitrogenatmosphere. Add oxalyl chloride (17.7 mL, 0.2 mol) over about 5 minutes.Stir at ambient temperature for 3 hours and evaporate the solvent invacuo to give the title compound.

PREPARATION 2 Synthesis of Phthalimido-(S)-phenyalanine amide ##STR43##

Combine N-phthaloyl-(S)-phenylalanine, acid chloride (100 mmol) andhexane (100 mL). Add a concentrated aqueous ammonia solution (30 mL) andstir rapidly. After 10 minutes, filter, rinse with diethyl ether andwater, and dry in vacuo to give the title compound as a solid.

PREPARATION 3 Synthesis of 2,6-Dicyano-piperidine

Combine sodium cyanide (12.25 g, 250 mmol) and water (40 mL). Addammonium chloride (20 g, 374 mmol) and 30% aqueous ammonia solution (35mL, 620 mmol). Cool in an ice-bath. Add glutaric dialdehyde (25 mL, 50%in water, 125 mmol). After 7 hours in an ice bath, cool in a bath usinga ice/methanol mixture to form a solid. Collect the solid by filtration,rinse with water, and dry to give the title compound.

EXAMPLE 1 (S)-N-2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl!-1,4-dihydro-pyridine##STR44##

Combine phthalimido-(S)-phenyalanine amide (3.0 g, 10 mmol) and asolution of glutaric dialdehyde (2.0 g; 50% by weight in water) indichloromethane (200 mL). Heat to reflux with azeotropic removal ofwater from the refluxate. Add p-toluenesulfonic acid (60 mg). Continueheating at reflux. Pass the refluxate through oven dried 4 Å molecularsieves. After 4 days, cool the reaction mixture to ambient temperature.Extract with 5% sodium bicarbonate solution. Extract the 5% sodiumbicarbonate solution with dichloromethane. Combine the organic layersand dry over Na₂ SO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 5%tetrahydrofuran/dichloromethane to give the title compound.

EXAMPLE 1.1 (S)-N-2-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl!-1,4-dihydro-pyridine

Combine phthalimido-(S)-phenylalanine amide (6.0 g, 20 mmol) and asolution of glutaric dialdehyde (4.0 mL, 50% by weight in water) indichloromethane (300 mL). Heat to reflux with azeotropic removal ofwater from the refluxate using a Dean-Stark trap. Add p-toluenesulfonicacid (600 mg). Continue heating at reflux with azeotropic removal ofwater. Replace the Dean-Stark trap with a Soxhlet extractor charged withphosphorous pentoxide and continue heating at reflux. After 24 hours,cool the reaction mixture to ambient temperature. Add basic alumina toform a slurry. Filter the slurry through a plug of silica gel and elutewith dichloromethane. Evaporate the filtrate in vacuo to give the titlecompound.

EXAMPLE 2 (S)-7-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,6,7,8,12b-hexahydro-6-oxopyrido2,1-a! 2!benzazepine ##STR45##

Add a solution of (S)-N-2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl!-1,4-dihydro-pyridine(1.1 g, 3.1 mmol) in dichloromethane (2 mL) to trifluoromethanesulfonicacid (1.2 mL). After 2.5 hours, add trifluoromethanesulfonic acid (1.2mL). After 4 hours, partition the reaction mixture between ethyl acetateand 5% sodium bicarbonate solution. Dry the organic layer over Na₂ SO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting sequentially with 10% ethyl acetate/hexaneand then 25% ethyl acetate/hexane to give the title compound.

EXAMPLE 2.1 (S)-7-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,6,7,8,12b-hexahydro-6-oxopyrido2,1-a! 2!benzazepine

Combine sulfuric acid (3.0 mL, 96%) and trifluoroacetic anhydride (300mL). Add (S)-N-2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl!-1,4-dihydro-pyridine(1.0 mmol). After 30 minutes, pour the reaction mixture into a mixtureof saturated aqueous sodium bicarbonate and ice. Extract with ethylacetate and then with methylene chloride. Combine the organic layers andfilter through a plug of silica gel. Rinse the silica gel withdichloromethane. Evaporate the filtrate in vacuo to give a residue.Chromatograph the residue on silica gel eluting sequentially with 10%ethyl acetate/hexane and then 25% ethyl acetate/hexane to give the titlecompound.

EXAMPLE 3 (S)-7-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine-4-carboxylic acid ##STR46##

Combine (S)-7-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,6,7,8,12b-hexahydro-6-oxopyrido2,1-a! 2!benzazepine (32 mg, 0.09 mmol) and sulfuric acid (1.0 mL,95-98%) in a pressure vessel. Add 96% formic acid (200 μL) and quicklyseal the vessel. After 18 hours, add water (10 mL). Extract the reactionmixture with ethyl acetate. Extract the organic layer with saturatedaqueous potassium carbonate solution (5×10 mL). Combine the aqueouslayers and carefully acidify with aqueous 12M hydrochloric acidsolution. Extract with chloroform (5×15 mL). Combine the organic layers,dry over MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel eluting with 2/1 ethylacetate/hexane containing 0.5% acetic acid to give the title compound.R_(f) =0.14 (silica gel, 2/1 ethyl acetate/hexane containing 0.5% aceticacid).

EXAMPLE 3.1 (S)-7-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine-4-carboxylic acid

Combine (S)-7-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,6,7,8,12b-hexahydro-6-oxopyrido2,1-a! 2!benzazepine (67 mg, 0.19 mmol) and sulfuric acid (2.0 mL,95-98%) in a pressure vessel. Add 96% formic acid (400 μL) and quicklyseal the vessel. After 18 hours, open the vessel cautiously and addice-cold water (5 mL). Extract the reaction mixture repeatedly withchloroform. Combine the organic layers, dry over MgSO₄, filter, andevaporate in vacuo to give a residue. Chromatograph the residue onsilica gel eluting with 2/1/0.01 ethyl acetate/hexane/acetic acid togive the title compound.

EXAMPLE 3.2 (S)-7-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine-4-carboxylic acid

Combine (S)-7-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,6,7,8,12b-hexahydro-6-oxopyrido2,1-a! 2!benzazepine (32 mg, 0.09 mmol) and sulfuric acid (1.0 mL,95-98%) in a pressure vessel. Add carbon monoxide (gas) by sparge to apressure of 45 psi. After 18 hours, add water (10 mL). Extract thereaction mixture with ethyl acetate. Extract the organic layer withsaturated aqueous potassium carbonate solution (5×10 mL). Combine theaqueous layers and carefully acidify with aqueous 12M hydrochloric acidsolution. Extract with chloroform (5×15 mL). Combine the organic layers,dry over MgSO₄, filter, and evaporate in vacuo to give a residue.Chromatograph the residue on silica gel to give the title compound.

EXAMPLE 3.3 (S)-7-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine-4-carboxylic acid

Combine (S)-7-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,6,7,8,12b-hexahydro-6-oxopyrido2,1-a! 2!benzazepine (800 mg, 2.2 mmol) and sulfuric acid (24 mL) in apressure vessel. Carefully, add formic acid (4.0 mL, 87 mmol) tominimize mixing and thereby the formation of carbon monoxide. Seal thepressure vessel and add carbon monoxide to 300 psi before stirring.(Caution, upon mixing a sharp rise in pressure will occur.) After 16hours, vent the vessel and add the reaction mixture to an ice/watermixture (160 mL). Extract repeatedly with ethyl acetate. Combine theorganic layers and extract repeatedly with aqueous 10% potassiumbicarbonate solution. Combine the potassium bicarbonate solution layersand cool in an ice-bath. Acidify to pH 1 using aqueous 6M hydrochloricacid solution. Extract the acidified aqueous layer repeatedly with ethylacetate. Combine the organic layers and extract with saturated aqueoussodium chloride solution, dry over MgSO₄, filter, and evaporate in vacuoto give the title compound.

EXAMPLE 4 Synthesis of N-2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl!-2-cyano-1,2,3,4-tetrahydropyridine##STR47##

Generate 2-cyano-1,2,3,4-tetrahydro-pyridine in situ, combine2,6-dicyano-piperidine (1.0 g, 7.4 mmol) tetrahydrofuran (20 mL). Coolto about -23° C. using a dry ice/carbon tetrachloride bath. Slowly, addpotassium t-butoxide (0.913 g, 95%, 8.14 mmol). Slow addition of thepotassium t-butoxide is required to minimize the formation ofby-products. After the addition of potassium t-butoxide is complete, thereaction mixture is stirred for 20-30 minutes to give a solution of2-cyano-1,2,3,4-tetrahydro-pyridine. Warm the solution to ambienttemperature. Add N-phthaloyl-(S)-phenylalanine, acid chloride (2.55 g,8.14 mmol) and N-methylmorpholine (0.8 mL, 7.4 mmol). After 2 hours,partition the reaction mixture between chloroform and and aqueous 1Msodium bicarbonate solution. Separate the organic layer, dry over MgSO₄,filter, and evaporate in vacuo to give a residue. Chromatograph theresidue on silica gel eluting with 25% ethyl acetate/hexane to give thetitle compound.

EXAMPLE 5 Synthesis of 4-cyano-(S)-7-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine ##STR48##

Combine N-2(S)-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)-1-oxo-3-phenylpropyl!-2-cyano-1,2,3,4-tetrahydro-pyridine(100 mg, 0.26 mmol), sulfuric acid (3 mL, 99.999%), and trifluoroaceticanhydride (0.03 mL). After 24 hours, the title compound is obtained as asolution.

EXAMPLE 6 (S)-7-(1,3-Dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine-(S)-4-carboxylic acid

Combine a solution of 4-cyano-(S)-7-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine as obtained in Example 5 and water (30 mL). After 3hours, extract the reaction mixture with chloroform. Separate theorganic layer, dry over Na₂ SO₄, filter, and evaporate in vacuo to givea residue (10:1 mixture of S:R isomers at the 4-position carboxylic acidas determined by NMR analysis). Chromatograph the residue on silica geleluting sequentially with ethyl acetate and then ethyl acetate/aceticacid 99/1 to give the title compound. α!² _(D) ^(O) =-60.74° (c=0.915,MeOH).

PREPARATION 4 Preparation of 4S- 4α, 7α(R*), 12bβ!!-7-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid Synthesis of 4S- 4α, 7α(R*),12bβ!!-7-(Amino)-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido 2,1-a!2!benzazepine-4-carboxylic acid

Combine 4S- 4α, 7α(R*), 12bβ!!-7-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)!-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine-4-carboxylic acid (1.63 kg, 4.03 mol),triethylamine (429 g, 4.24 mol), and methanol (5.59 kg). Add hydrazinemonohydrate (241 g, 4.82 mol). Heat at reflux. After 3 hours, cool to60° C. and pour the reaction mixture into a mixture of water (7.326 kg)and aqueous 37% hydrochloric acid solution (821 g). Evaporate in vacuoat 50° C. until the reaction mixture is reduced about 7.8 kg. Dilute thereaction mixture with water (8.078 kg) and adjust the pH to about 2.82using aqueous 37% hydrochloric acid solution. Heat to 50° C. After 1hour, filter to remove the solids and rinse with water (pH adjusted to2.5 with hydrochloric acid, 1.502 kg). Combine the filtrate and therinse. Adjust the pH to 7.22 using triethylamine. Evaporate in vacuo at60° C. until the reaction mixture is reduced to about 4.65 kg to obtaina slurry. Dilute the slurry with isopropanol (3.53 kg) and stir for 30minutes. Cool to 5° C. to obtain a solid. Collect the solid byfiltration, rinse with isopropanol, and dry to give the title compound(933 g, 84.4%).

Synthesis of 4S- 4α, 7α(R*), 12bβ!!-7-(1-Oxo-2(R)-bromo-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid

Mix 3-phenyl-2(R)-bromopropionic acid (967 g, 4.22 mol), tetrahydrofuran(7.74 kg) and N-hydroxysuccinimide (607 g, 5.27 mol) and cool to 5° C.Add, by slow addition over 2.5 hours, a solution of1,3-dicyclohexylcarbodiimide (828 g, 4.01 mol) in tetrahydrofuran (1.936kg), maintaining the temperature between -3° and 3° C. Stir for 19hours, remove 2,3-dicyclohexylurea by vacuum filtration and wash thefilter cake with tetrahydrofuran (1.927 kg). Place the filtrate and washin a 50 L bottom-drain round-bottom flask, add 4S- 4α, 7α(R*),12bβ!!-7-(amino)-1,2,3,4,6,7,8,9,12b-octahydro-6-oxo-pyrido 2,1-a!2!benzazepine-4-carboxylic acid (869 g, 3.17 mol) and stir at 22° C. for5.5 hours. Add triethylamine (77 g, 0.76 mol) and stir for an additional17 hours at 22° C. Dilute with ethyl acetate (10.427 kg), wash withwater (9.94 kg) with 37% hydrochloric acid (214.2 g) and sodium chloride(418 g), then with 12.328 kg water with sodium chloride (418 g). Dry(MgSO₄), filter and wash the filter cake with ethyl acetate (2.193 kg).Evaporate the solvent in vacuo, add isopropanol (4.210 kg), stir at12°-16° C. for 17 hour, chill and isolate the product by vacuumfiltration. Wash with isopropanol (621 g) and dry to give the titlecompound (940 g, 61%).

Synthesis of 4S- 4α, 7α(R*), 12bβ!!-7-(1-Oxo-2(S)-acetylthio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid

Mix 4S- 4α, 7α(R*), 12bβ!!-7-(1-oxo-2(R)-bromo-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid (1.052 kg, 2.17 mol), acetone(13.256 kg) and thiolacetic acid (207.1 g, 2.72 mol). Cool to -2° C. andadd, over approximately 10 minutes, a solution of potassium hydroxide(279.5 g) in water (270 g). Stir at -4° C. for 23 hours, add 1.054 kgwater containing 37% hydrochloric acid (210 g) and evaporate the solventin vacuo. Dissolve the solid residue in toluene (11.517 kg) at 43° C.,transfer to a 22 L bottom-drain round bottom flask and wash with water(4.067 kg). Wash at 41° C. with 4.099 kg water containing sodiumchloride (213 g). Evaporate the solvent in vacuo, dissolve the solidresidue in toluene (10.239 kg), filter and cool. After cooling to -2°C., collect the solid by vacuum filtration, wash with toluene (1.103 kg)and dry under vacuum at up to 80° C. to give the title compound (859 g,82.5%).

Preparation of 4S- 4α, 7α(R*), 12bβ!!-7-(1-Oxo-2(S)-thio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid

Dissolve 4S- 4α, 7α(R*), 12bβ!!-7-(1-oxo-2(S)-acetylthio-3-phenylpropyl)amino!-1,2,3,4,6,7,8,12b-octahydro-6-oxo-pyrido2,1-a! 2!benzazepine-4-carboxylic acid (57 mg, 0.12 mmol) indeoxygenated methanol (3 mL) containing lithium hydroxide (0.25 mL, 1Min water, 0.25 mmol). Stir for 30 minutes under argon atmosphere atambient temperature. Reduce in volume to 1.5 mL in vacuo, then add, bydropwise addition, to a rapidly stirring solution of 2M hydrochloricacid (2 mL). Collect the resulting precipitate, wash with water and dryin a vacuum dessicator for 1 hour. Dry at 35° C. overnight to give thetitle compound as a white electrostatic powder.

What is claimed is:
 1. A process for preparing a compound of the formula##STR49## wherein G completes an aromatic ring selected from the groupconsisting of ##STR50## wherein X₁ is selected from the group consistingof S and NH;X₂ is selected from the group consisting of S, O, and NH;and R is selected from the group consisting of hydrogen, hydroxy,phenyl, and C₁ -C₄ alkoxy;comprising: (a) reacting a phthalimido arylamino acid derivative of the formula ##STR51## wherein A is selectedfrom the group consisting of --OH, --Cl, --Br, anhydride, mixedanhydride, and activated ester; Ar is a radical selected from the groupconsisting of ##STR52## wherein X₁ is selected from the group consistingof S and NH; X₂ is selected from the group consisting of S, O, and NH;and R is selected from the group consisting of phenyl and C₁ -C₄alkoxy;with 2-cyano-1,2,3,4-tetrahydro-pyridine to give a2-cyano-1,2,3,4-tetrahydro-pyridine derivative of the formula ##STR53##wherein Ar is as defined above; (b) reacting the2-cyano-1,2,3,4-tetrahydro-pyridine derivative with an appropriatecyclizing acid to give a 4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido2,1-a! 2!benzazepine of the formula ##STR54## wherein G is as definedabove; (c) hydrolyzing the4-cyano-1,2,3,4,6,7,8,12b-octahydro-6-oxopyrido 2,1-a! 2!benzazepine. 2.A process according to claim 1 wherein the appropriate cyclizing acid isa trifluoromethanesulfonic acid/trifluoroacetic anhydride mixture.
 3. Aprocess according to claim 1 wherein the appropriate cyclizing acid issulfuric acid/trifluoroacetic anhydride mixture.
 4. A process accordingto claim 1 wherein the 2-cyano-1,2,3,4-tetrahydro-pyridine is generatedin situ from 2,6-dicyano-piperidine.